Schizophrenia (SZ) is a debilitating mental disorder with significant and complex pathophysiology in the prefrontal cortex (PFC). Several aspects of this cortical pathology have been linked to deficits in executive functions such as working memory, attention, and cognitive flexibility. A more thorough understanding of the neurochemical mechanisms contributing to these cognitive disorders is critical, as conventional antipsychotics are not particularly effective in alleviating these impairments, and since the severity of these deficits is predictive of the patient's ability to integrate into society. The activity of 17 nicotinic receptors (17nAChR) in the PFC has been positively linked to performance in a number of behavioral tasks that measure executive cognitive functions. Conversely, dysregulation of cortical 17nAChRs has been implicated in the etiology of SZ. Kynurenic acid (KYNA) is an astrocyte-derived neuromodulator that, at endogenous concentrations, inhibits 17nAChR activity in several brain regions, including the PFC. KYNA levels are elevated in the PFC of individuals with schizophrenia, and this increase is not secondary to antipsychotic medication. This project is designed to define the role of KYNA in the modulation of basal and stimulated glutamate and acetylcholine (ACh) levels in the PFC and in the mediation of a prefrontally- mediated cognitive behavior (perceptual set-shifting). Our preliminary data in rats demonstrate that fluctuations in the endogenous levels of KYNA modulate levels of glutamate and ACh in the PFC. The proposed experiments will use complementary biochemical, pharmacological and behavioral methods, and the synergistic expertise of two experienced PIs, to evaluate key chemical events and functional implications of this link between KYNA, ACh and glutamate in the rat PFC. Aim #1 will utilize in vivo microdialysis to test the hypothesis that fluctuations in endogenous KYNA levels within the PFC influence glutamate and ACh levels under conditions of basal levels of 17nAChR activity. We will also determine whether these effects, as hypothesized, can be traced to KYNA's ability to antagonize the 17nAChR and whether the KYNA-related modulation of ACh levels is mediated by local glutamate. Aim #2 will determine, as a prelude to subsequent aims in task-performing rats, the extent to which KYNA retains the ability to modulate prefrontal glutamate and ACh release under two conditions that activate the 17nAChR (a centrally-administered drug and a behavioral conditioning paradigm). Aim #3 extends these neurochemical studies to the realm of cognitive behavior and will test the hypothesis that elevations in cortical KYNA levels selectively impair the ability of rats to perform in a perceptual set-shifting task, which is dependent upon the integrity of neurotransmission in the PFC. We will also determine the relative roles of diminished cholinergic and glutamatergic function in this KYNA-induced behavioral deficit. This is especially relevant to the pathophysiology of SZ which is associated with excessive KYNA levels in the PFC, abnormal cortical glutamatergic and nicotinergic transmission, and pronounced impairments in set- shifting tasks. Finally, since prolonged elevations of cortical KYNA levels are seen in SZ, we will, in Aim #4, study the biochemical and functional consequences of persistent increases in brain KYNA levels. These chronic effects will be evaluated both in control animals and in rats treated with typical (haloperidol) or atypical (clozapine) neuroleptic drugs in combination with an adjunctive therapy targeting the 17nAChR with a clinically used cognition-enhancing drug (galantamine). Collectively, the proposed experiments will test the new hypothesis that fluctuations in astrocyte-derived KYNA levels potently modulate cortical neurotransmission and prefrontally-mediated cognitive behavior. We will use these findings to generate an experimental platform for testing the therapeutic efficacy of KYNA-based treatments in alleviating the cognitive deficits seen in SZ. PUBLIC HEALTH RELEVANCE: Individuals with schizophrenia (SZ), a debilitating psychiatric disorder, show complex impairments of the prefrontal cortex (PFC). These cortical abnormalities are responsible for the deficits in executive functions seen in most patients and are likely related to a dysfunction of specific receptors for the neurotransmitters glutamate and acetylcholine (ACh). Notably, enhanced activity of the same receptors is known to improve performance in cognitive functions. Kynurenic acid (KYNA) is a glial cell-derived neuromodulator that is present in the mammalian brain and has the capacity to modulate cortical glutamatergic and cholinergic neurotransmission. Interestingly, KYNA levels are elevated in the brain of SZ patients and may thereby impair glutamate and ACh function and, as a result, prefrontally-mediated cognitive behaviors. This hypothesis will be tested experimentally in the proposed project. Collectively, the experiments will a) provide new insights into the neurochemical effects of KYNA;b) explore the role of glial cells in the regulation of attention and cognitive flexibility;c) evaluate the construct validity of chronic elevations of KYNA in the brain for the study of SZ;and d) begin to examine whether treatment- induced reductions of KYNA levels in the brain constitute an efficacious strategy for the treatment of cognitive deficits in SZ.